In 2010, we published the first description of a genetically unique strain of Lassa virus isolated from Mastomys natalensis captured in Mali, an area previously thought to be free of Lassa virus. Over the last seven years we have continued to conduct field studies mapping the geographic distribution of Lassa virus in peridomestic settings across sub-Saharan Mali. With a better understanding of the regions endemic for this virus in Mali, the Lassa program has transitioned into studies aimed at defining the infection dynamics and transmissibility of Lassa in the natural rodent hosts. For this we have established a colony of Mastomys natalensis at the Rocky Mountain Laboratories. Several studies have shown that the animals can be persistently infected with different Lassa strains without showing obvious clinical signs but virus shedding through different routes (yet unpublished; manuscripts under preparation). Thus, this colony provides a unique tool for future studies Lassa virus infection in the natural host. We also have started to define the incidence rates of Lassa virus infection in humans in southern Mali. Two human serosurvey studies were conducted at three sites; IgG seroprevalence was found at all sites ranging from 16-44%. Interestingly, in the follow-up study we identified an annual infection rate of 6.3%. As there are no reports of Lassa fever in Mali this indicates that asymptomatic and mild infections are frequently occurring. A new two-part study covering a larger geographic area is currently being planned. We will examine a cross-section of the population as a whole looking for Lassa virus prevalence and collect clinical samples to determine the prevalence of Lassa Fever. This study will confirm and expand upon our previous results and identify human infections to determine the public health importance of Lassa virus infections in Mali. As mentioned above, we do have a Lassa virus isolate from Mali (designated Soromba). Multiple studies have been performed at Rocky Mountain Laboratories defining the pathogenic potential in animal models as well as the efficacy of vaccines and antivirals. Lassa-Soromba seems to be less virulent in animal models and presents with an atypical clinical disease in the cynomolgus macaque model supporting the idea of the circulation of a distinct and less pathogenic Lassa strain in southern Mali. A live-attenuated recombinant vaccine platform expressing the Lassa virus glycoproteins (rVSV-Lassa) showed efficacy against several Lassa isolates including Lassa-Soromba. This vaccine has been GMP-produced and the GMP lot is currently being sterility tested for a future phase I clinical trial. More recently, we have evaluated the efficacy of ribavirin and favipiravir as antivirals against Lassa virus in two animal models (guinea pig and nonhuman primate) with favipiravir being superior over ribavirin. The Mali field program has expanded to include other zoonotic viruses including surveillance for additional arenaviruses (Lassa, Lujo), bunyaviruses (hantaviruses, Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus), flaviviruses (Dengue, Zika), and coronavirus (MERS-CoV). We have started to also test serum/blood from humans and livestock and wildlife species to determine the prevalence and importance of zoonotic pathogens for animal and public health in Mali. As of today, we could demonstrate MERS-CoV infections in Malian camels and high CCHFV infection rates in Malian cattle. For humans, we could establish serologic evidence for flavivirus (Dengue, Zika), bunyaviruses (hantavirus), and togaviruses (Chikungunya) infections as well as infections with Leptospira spp.; all contributing to human illness in Mali. These results implying that several of these zoonotic pathogens are widely distributed yet underreported throughout West Africa This program also includes education and training of young Malian scientists.